Chemoembolisation

Abstract

A composition for chemoembolotherapy of solid tumors comprises particles of a water-insoluble water-swellable synthetic anionic polymer and, absorbed therein an anthracycline. Suitably the polymer is a poly(vinyl alcohol) based polymer and the drug is doxorubicin.

What is claimed is: 
     
       1. A composition comprising microspheres having a matrix of water-swellable water-insoluble polymer and, absorbed in the matrix, a water-soluble therapeutic agent, wherein the polymer has an overall anionic charge at a pH in the range 6 to 8, wherein the microspheres, when swollen to equilibrium in water have particle sizes in the range 40-1500 μm, wherein the therapeutic agent is an anthracycline compound having at least one amine group, and wherein the polymer comprises a covalently cross-linked polyvinyl alcohol (PVA) formed by copolymerizing a polyvinyl alcohol macromer having at least two pendant vinylic or acrylic groups per molecule with ethylenically unsaturated monomers including an anionic monomer. 
     
     
       2. A composition according to  claim 1  in which the anthracycline is a compound of the general formula II 
       
         
           
           
               
               
           
         
       
     
     
       3. The composition according to  claim 2  wherein the compound of general formula II is doxorubicin. 
     
     
       4. The composition according to  claim 1  wherein the microspheres are swollen with and suspended in an aqueous liquid. 
     
     
       5. The composition according to  claim 4  further comprising an imaging agent. 
     
     
       6. The composition according to  claim 5  wherein the imaging agent is a radiopaque agent. 
     
     
       7. A method of embolising a solid tumour comprising the steps of administering a composition according to  claim 4  into a blood vessel of a patient to embolise the solid tumour. 
     
     
       8. The method according to  claim 7  wherein the tumour is hepatocellular carcinoma. 
     
     
       9. The composition according to  claim 1  wherein the microspheres are in the form of a pumpable slurry comprising microspheres swollen with aqueous liquid. 
     
     
       10. The composition according to  claim 9 , which is filled into a storage container and is sterile. 
     
     
       11. The composition according to  claim 10  wherein the storage container is a syringe. 
     
     
       12. The composition according to  claim 1  which is substantially dry. 
     
     
       13. A process for producing a composition according to  claim 1  comprising the steps:
 providing microspheres of a water-swellable, water-insoluble polymer, wherein the polymer has an overall anionic charge at a pH in the range 6 to 8, wherein the microspheres, when swollen to equilibrium in water have particle sizes in the range 40-1500 μm and wherein the water-swellable water insoluble polymer comprises a covalently cross-linked polyvinyl alcohol (PVA) formed by copolymerizing a polyvinyl alcohol macromere having at least two pendant vinylic or acrylic groups per molecule with ethylenically unsaturated monomers including an anionic monomer; and 
 contacting the microspheres with a solution of an anthracycline having at least one amine group in the presence of water; and
 absorbing anthracycline into the matrix of the polymer. 
 
 
     
     
       14. The process according to  claim 13  in which the contacting is carried out by suspending the microspheres in an aqueous solution of the anthracycline. 
     
     
       15. The process according to  claim 14  comprising the further step of recovering the microspheres of polymer with anthracycline absorbed in the matrix from the suspension. 
     
     
       16. The process according to  claim 15  comprising the further step of drying the microspheres. 
     
     
       17. The process according to  claim 16  wherein the drying is freeze-drying. 
     
     
       18. A method of embolising a solid tumour comprising the steps of mixing a composition according to  claim 1  with a contrast agent and administering the mixture into a blood vessel of a patient to embolise the solid tumour. 
     
     
       19. The method according to  claim 18  wherein the tumour is hepatocellular carcinoma. 
     
     
       20. The composition according to  claim 1 , wherein the level of anion in the polymer matrix is in the range 0.1-10 meq/g. 
     
     
       21. The composition according to  claim 20 , wherein the level of the anion in the polymer matrix is at least 1.0 meq/g. 
     
     
       22. The composition according to  claim 1 , wherein the pendant acrylic groups are formed by reacting acrylic or methacrylic acid with polyvinyl alcohol to form ester linkages through one or more of the hydroxyl groups. 
     
     
       23. The composition according to  claim 1 , wherein the polyvinyl alcohol macromer has average molecular weight in the range 1,000 to 500,000 Da. 
     
     
       24. The composition according to  claim 23 , wherein the polyvinyl alcohol macromer has average molecular weight in the range 10,000 to 100,000 Da. 
     
     
       25. The composition according to  claim 1 , wherein in the ethylenically unsaturated monomer, the anionic monomer is present in an amount in the range 10 to 100 mole %. 
     
     
       26. The composition according to  claim 25 , wherein the anionic monomer is present in an amount of at least 25 mole %. 
     
     
       27. The composition according to  claim 1 , wherein the weight ratio of the polyvinyl alcohol macromer to other monomer is in the range of 50:1 to 1:5. 
     
     
       28. The composition according to  claim 27 , wherein the weight ratio of the polyvinyl alcohol macromer to other monomer is in the range of 20:1 to 1:2. 
     
     
       29. The composition according to  claim 1 , in which the anionic monomer has the general formula I:
   Y 1 BQ 
 wherein 
 Y 1  is a group of the formula CH 2 ═CRCOA- in which R is selected from H and methyl; and A is NH; 
 B is an alkanediyl group of 1 to 12 carbon atoms; and 
 Q is a sulphonate group. 
 
     
     
       30. A composition according to  claim 29 , wherein the anionic monomer is 2-acrylamido-2-methyl-1-propane-sulphonic acid (AMPS). 
     
     
       31. The composition according to  claim 1 , wherein the water-insoluble water-swellable polymer has an equilibrium water content measured by gravimetric analysis in the range of 40-99 wt %. 
     
     
       32. The composition according to  claim 31 , wherein the water-insoluble water-swellable polymer has an equilibrium water content measured by gravimetric analysis in the range of 75-95 wt %.